Zusammenfassung
Entzündungsprozesse sind sowohl beim Asthma als auch bei der COPD von wesentlicher Bedeutung. In der Praxis werden diese Erkrankungen häufig mit Kortikosteroiden behandelt. Eine Messung von Art und Ausmaß der Atemwegsentzündung im Rahmen der Diagnostik, Verlaufskontrolle und Optimierung der Therapie erfolgt aber meist nicht, obwohl mittlerweile eine Reihe von Studien belegen, dass Patienten von einer solchen Messung profitieren können. Bei vielen Atemwegserkrankungen ist die eosinophile Entzündung von besonderer Bedeutung. Sie findet sich nicht nur bei Allergen-induzierten Erkrankungen, sondern kann auch bei chronisch-obstruktiver Bronchitis, z. B. während einer Exazerbation, auftreten und spricht in der Regel gut auf eine Kortikosteroidbehandlung an. Frühzeitige Informationen über Art und Ausmaß einer Entzündung erleichtern deshalb nicht nur die differenzialdiagnostische Einordnung einer Erkrankung, sondern könnten auch den Behandlungserfolg steigern. Der nicht-invasive Nachweis einer eosinophilen Atemwegsentzündung mittels Sputuminduktion ist für den klinischen Alltag zu aufwendig. Eine eosinophile Entzündung korreliert aber gut mit der Konzentration des ausgeatmeten Stickstoffmonoxids. Für dessen Nachweis gibt es mittlerweile speziell für die klinische Praxis entwickelte Analysatoren, die es erlauben, durch eine sehr einfache, z. B. auch für Kinder geeignete Methode, innerhalb weniger Minuten eine Analyse durchzuführen. Im ersten Teil dieses Reviews sollen zunächst einige für die adäquate Interpretation von Stickstoffmonoxid-Werten in der täglichen Praxis wichtige Grundlagen erörtert werden. Ausgehend von den bisher zur Einschätzung der klinischen Wertigkeit der Stickstoffmonoxidanalyse publizierten Arbeiten sollen im zweiten Teil die klinischen Möglichkeiten und Grenzen der Methode diskutiert werden.
Abstract
Airway inflammation plays a major role in the pathology of both asthma and COPD and is the target of corticosteroid treatment. In daily routine practise, however, airway inflammation is still not often considered by pneumologists to support the diagnostic process or to aid in disease management, despite studies showing that patients could benefit. Eosinophilic airway inflammation is of special interest, as it is not restricted to allergen-induced airway diseases, and because it generally responds well to anti-inflammatory treatment with corticosteroids. Therefore, the early detection of this kind of underlying inflammatory process can have a positive impact on finding a diagnosis as well as for disease management. The non-invasive detection of eosinophilic airway inflammation using induced sputum is too time consuming and therefore too expensive in outpatient settings. As sputum eosinophils correlate with the concentration of exhaled nitric oxide (FeNO), its measurement could serve as a more economic alternative, especially as new small handheld analysers are available now, that allow the rapid FeNO analysis, even in children. This review will cover some basics and technical aspects of FeNO measurements, which should be known to correctly interprete results in clinical practise. In the second part, the clinical value and the limits of FeNO measurements, as well as the potential interpretation of results are discussed based on recently published literature.
Literatur
1
Hamid Q, Springall D R, Riveros-Moreno V. et al .
Induction of nitric oxide synthase in asthma.
Lancet.
1993;
342
1510-1513
2
Redington A E, Meng Q H, Springall D R. et al .
Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment.
Thorax.
2001;
56
351-357
3
Lundberg J O, Farkas-Szallasi T, Weitzberg E. et al .
High nitric oxide production in human paranasal sinuses.
Nat Med.
1995;
1
370-373
4
Jörres R A.
Modelling the production of nitric oxide within the human airways.
Eur Respir J.
2000;
16
555-560
5
Silkoff P E, McClean P A, Slutsky A S. et al .
Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.
Am J Respir Crit Care Med.
1997;
155
260-267
6
ATS/ERS .
Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children.
Am J Respir Crit Care Med.
2005;
171
912-930
7
Olin A C, Rosengren A, Thelle D S. et al .
Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample.
Chest.
2006;
130
1319-1325
8
Silkoff P E, Wakita S, Chatkin J. et al .
Exhaled nitric oxide after beta2 -agonist inhalation and spirometry in asthma.
Am J Respir Crit Care Med.
1999;
159
940-944
9
Beier J, Beeh K M, Kornmann O. et al .
Sputum induction leads to a decrease of exhaled nitric oxide unrelated to airflow.
Eur Respir J.
2003;
22
354-357
10
Georges G, Bartelson B B, Martin R J. et al .
Circadian variation in exhaled nitric oxide in nocturnal asthma.
J Asthma.
1999;
36
467-473
11
Yates D H, Breen H, Thomas P S.
Passive smoke inhalation decreases exhaled nitric oxide in normal subjects.
Am J Respir Crit Care Med.
2001;
164
1043-1046
12
Kharitonov S A, Robbins R A, Yates D. et al .
Acute and chronic effects of cigarette smoking on exhaled nitric oxide.
Am J Respir Crit Care Med.
1995;
152
609-612
13
De Gouw H W, Grunberg K, Schot R. et al .
Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects.
Eur Respir J.
1998;
11
126-132
14
Kharitonov S A, Yates D, Barnes P J.
Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections.
Eur Respir J.
1995;
8
295-297
15
Olin A C, Aldenbratt A, Ekman A. et al .
Increased nitric oxide in exhaled air after intake of a nitrate-rich meal.
Respir Med.
2001;
95
153-158
16
Bruce C, Yates D H, Thomas P S.
Caffeine decreases exhaled nitric oxide.
Thorax.
2002;
57
361-363
17
Deykin A, Massaro A F, Coulston E. et al .
Exhaled nitric oxide following repeated spirometry or repeated plethysmography in healthy individuals.
Am J Respir Crit Care Med.
2000;
161
1237-1240
18
Müller K C, Jörres R A, Magnussen H. et al .
Comparison of exhaled nitric oxide analysers.
Respir Med.
2005;
99
631-637
19
Olin A C, Alving K, Toren K.
Exhaled nitric oxide: relation to sensitization and respiratory symptoms.
Clin Exp Allergy.
2004;
34
221-226
20
Malmberg L P, Petays T, Haahtela T. et al .
Exhaled nitric oxide in healthy nonatopic school-age children: determinants and height-adjusted reference values.
Pediatr Pulmonol.
2006;
41
635-642
21
Buchvald F, Baraldi E, Carraro S. et al .
Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.
J Allergy Clin Immunol.
2005;
115
1130-1136
22
Olivieri M, Talamini G, Corradi M. et al .
Reference values for exhaled nitric oxide (reveno) study.
Respir Res.
2006;
7
DOI: 10.1186/1465-9921-7-94
23 Revised GINA guidelines 2006 .Global initiative for asthma, National Institutes of Health, National Heart, Lung and Blood Institute. NIH Publication No 02-3659 2002
24
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease .
NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.
Am J Respir Crit Care Med.
2001;
163
1256-1276; For the update of definitions (2004) see: http://www.goldcopd.com/
25
Barnes P J, Chowdhury B, Kharitonov S A. et al .
Pulmonary biomarkers in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med.
2006;
174
6-14
26
Grönke L, Kanniess F, Holz O. et al .
The relationship between airway hyper-responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease.
Clin Exp Allergy.
2002;
32
57-63
27
Alving K, Janson C, Nordvall L.
Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children.
Respir Res.
2006;
7
DOI: 10.1186/1165-9921-7-67
28
Pijnenburg M W, Hofhuis W, Hop W C. et al .
Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.
Thorax.
2005;
60
215-218
29
Pijnenburg M W, Bakker E M, Hop W C. et al .
Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial.
Am J Respir Crit Care Med.
2005;
172
831-836
30
Zacharasiewicz A, Wilson N, Lex C. et al .
Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children.
Am J Respir Crit Care Med.
2005;
171
1077-1082
31
Smith A D, Cowan J O, Brassett K P. et al .
Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.
N Engl J Med.
2005;
352
2163-2173
32
Gibson P G, Fujimura M, Niimi A.
Eosinophilic bronchitis: clinical manifestations and implications for treatment.
Thorax.
2002;
57
178-182
33
Brightling C E, Green R H, Pavord I D.
Biomarkers predicting response to corticosteroid therapy in asthma.
Treat Respir Med.
2005;
4
309-316
34
Pizzichini M M, Pizzichini E, Parameswaran K. et al .
Nonasthmatic chronic cough: No effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia.
Can Respir J.
1999;
6
323-330
35
Pavord I D, Brightling C E, Woltmann G. et al .
Non-eosinophilic corticosteroid unresponsive asthma.
Lancet.
1999;
353
2213-2214
36
Green R H, Brightling C E, McKenna S. et al .
Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.
Lancet.
2002;
360
1715-1721
37
Berry M A, Shaw D E, Green R H. et al .
The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma.
Clin Exp Allergy.
2005;
35
1175-1179
38
Smith A D, Cowan J O, Brassett K P. et al .
Exhaled nitric oxide: a predictor of steroid response.
Am J Respir Crit Care Med.
2005;
172
453-459
39
Szefler S J, Phillips B R, Martinez F D. et al .
Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.
J Allergy Clin Immunol.
2005;
115
233-242
40
Little S A, Chalmers G W, MacLeod K J. et al .
Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma.
Thorax.
2000;
55
232-234
41
Beck-Ripp J, Griese M, Arenz S. et al .
Changes of exhaled nitric oxide during steroid treatment of childhood asthma.
Eur Respir J.
2002;
19
1015-1019
42
Jones S L, Kittelson J, Cowan J O. et al .
The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control.
Am J Respir Crit Care Med.
2001;
164
738-743
43 Pavord I. The new paradigm: assessing airway inflammation rather than diagnostic labelling is a movement not a fad. 2006: http://www.ersnet.org/ers/lr/browse/
44
Dupont L J, Demedts M G, Verleden G M.
Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma.
Chest.
2003;
123
751-756
45
Smith A D, Cowan J O, Filsell S. et al .
Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests.
Am J Respir Crit Care Med.
2004;
169
473-478
46
Ichinose M, Sugiura H, Yamagata S. et al .
Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways.
Eur Respir J.
2003;
22
457-461
47
Wewel A R, Crusius J A, Gatzemeier U. et al .
Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy.
Eur Respir J.
2006;
27
1033-1039
48
Brightling C E, Monteiro W, Ward R. et al .
Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.
Lancet.
2000;
356
1480-1485
49
Zietkowski Z, Kucharewicz I, Bodzenta-Lukaszyk A.
The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease.
Respir Med.
2005;
99
816-824
50
Kharitonov S A, Barnes P J.
Clinical aspects of exhaled nitric oxide.
Eur Respir J.
2000;
16
781-792
51
Haley K J, Drazen J M.
Inflammation and airway function in asthma: what you see is not necessarily what you get.
Am J Respir Crit Care Med.
1998;
157
1-3
52
Pizzichini M M, Pizzichini E, Clelland L. et al .
Prednisone-dependent asthma: inflammatory indices in induced sputum.
Eur Respir J.
1999;
13
15-21
53
Leuppi J D, Salome C M, Jenkins C R. et al .
Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids.
Am J Respir Crit Care Med.
2001;
163
406-412
54
Deykin A, Lazarus S C, Fahy J V. et al .
Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids.
J Allergy Clin Immunol.
2005;
115
720-727
55
Jatakanon A, Lim S, Barnes P J.
Changes in sputum eosinophils predict loss of asthma control.
Am J Respir Crit Care Med.
2000;
161
64-72
56
Jayaram L, Pizzichini M M, Cook R J. et al .
Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.
Eur Respir J.
2006;
27
483-494
57
Kharitonov S A, Yates D H, Barnes P J.
Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.
Am J Respir Crit Care Med.
1996;
153
454-457
58
Jones S L, Herbison P, Cowan J O. et al .
Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship.
Eur Respir J.
2002;
20
601-608
59
Shaw D E, Berry M E, Thomas M. et al .
Asthma exacerbations and exhaled nitric oxide: a randomised controlled trial.
Eur Respir J.
2006;
28
572s
60
Djukanovic R, Sterk P J, Fahy J V. et al .
Standardised methodology of sputum induction and processing.
Eur Respir J.
2002;
20
1S-55S
61
Lex C, Ferreira F, Zacharasiewicz A. et al .
Airway Eosinophilia in Children with Severe Asthma: Predictive Values of Noninvasive Tests.
Am J Respir Crit Care Med.
2006;
174
1286-1291
62
Haldar P, Haldar M, Green R H. et al .
Discordance between sputum eosinophil counts and exhaled nitric oxide levels in asthma.
Eur Respir J.
2006;
28
113s
63
Holz O, Jörres R A.
[Non-invasive methods for monitoring airway inflammation: a comparison of expenditures, gain and clinical value].
Pneumologie.
2004;
58
510-515
64
Taylor D R, Pijnenburg M W, Smith A D. et al .
Exhaled nitric oxide measurements: clinical application and interpretation.
Thorax.
2006;
61
817-827
65
Seiler T, Holz O, Karmeier A. et al .
Sputum-Zytologie in der klinischen Praxis.
Pneumologie.
2005;
59
S59
66
Hargreave F E, Parameswaran K.
Problems with using exhaled nitric oxide to guide asthma treatment.
J Allergy Clin Immunol.
2006;
117
1511-1512
67
Holz O, Mücke M, Zarza P. et al .
Freezing of homogenized sputum samples for intermittent storage.
Clin Exp Allergy.
2001;
31
1328-1331
Dr. rer. nat. Olaf Holz
Forschungslabor, Krankenhaus Großhansdorf, Zentrum für Pneumologie und Thoraxchirurgie
Wöhrendamm 80
22927 Großhansdorf
Email: o.holz@pulmoresearch.de; olaf.holz@t-online.de